Crry deficiency in complement sufficient mice: C3 consumption occurs without associated renal injury.
The rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry) is critical for complement homeostasis. Gene deletion is 100% embryonically lethal; Crry-deficient (Crry(-/-)) mice were rescued by back-crossing onto C3 deficiency, confirming that embryo loss was complement mediated. In order to rescue viable Crry(-/-) mice without deleting C3, we have tested inhibition of C5 during gestation. Crry(+/-) females were given neutralizing anti-C5 mAb immediately prior to mating with Crry(+/-) males and C5 inhibition maintained through pregnancy. A single, healthy Crry(-/-) female was obtained and mating with Crry(+/-) males yielded healthy litters containing equal numbers of Crry(+/-) and Crry(-/-) pups. Inter-crossing Crry(-/-) mice yielded healthy litters of expected size. Although the mice were not anemic, exposure of Crry(-/-) erythrocytes to normal mouse serum caused C3 deposition and lysis, while transfusion into normal or C6(-/-) mice resulted in rapid clearance. Complement activity and C3 levels in Crry(-/-) mice were markedly reduced. Comparison with factor H deficient (CfH(-/-)) mice revealed similar levels of residual C3; however, unlike the CfH(-/-) mice, Crry(-/-) mice showed no evidence of renal injury, demonstrating distinct roles for these regulators in protecting the kidney.
Ruseva
Marieta M
MM
Complement Biology Group, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Hughes
Timothy R
TR
Donev
Rossen M
RM
Sivasankar
Baalasubramanian
B
Pickering
Matthew C
MC
Wu
Xiaobo
X
Harris
Claire L
CL
Morgan
B Paul
BP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003176:Complement C3 / Q000235:genetics / Q000276:immunology*; D003182:Complement C5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D003183:Complement C6 / Q000235:genetics / Q000276:immunology; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D020964:Embryo Loss / Q000235:genetics / Q000276:immunology; D005260:Female; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D007668:Kidney / Q000276:immunology* / Q000293:injuries; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011951:Receptors, Complement / Q000235:genetics / Q000276:immunology*; D017463:Receptors, Complement 3b
D000911:Antibodies, Monoclonal; D003176:Complement C3; D003182:Complement C5; D003183:Complement C6; C081470:Cr1l protein, mouse; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D017242:Complement Factor H